The compounds of formula (I) are new synthetic compounds having hypolipidemic activity. The compounds of formula (I) are used primarily for triglyceride lowering, with concomitant beneficial effect on glucose lowering and cholesterol lowering.
The structural formula of compounds of formula (I) is shown below.
wherein ‘R’ is selected from hydroxy, hydroxyalkyl, acyl, alkoxy, alkylthio, thioalkyl, aryloxy, arylthio and M+ represents suitable metal cations such as Na+, K+, Ca+2, Mg+2 and the like. Preferably, R is selected from alkylthio or thioalkyl groups; most preferably R represents —SCH3. The Mg+2 salt is preferred. The compounds of formula (I) are generally insoluble in water, but freely soluble in dimethyl sulfoxide, dichloromethane & slightly soluble in methanol and IPA.
The compounds of formula (I) are susceptible to oxidation, alkaline & acid hydrolysis and stress degradation during synthesis, purification and storage of the drug substance or when formulated as a dosage form. Sulfoxide and sulfone derivatives are the potential oxidized product.
The handling and storage particularly in the bulk form of pharmaceutically active ingredients which are sensitive to oxidation is difficult. Special handling is necessary and often the oxidation-sensitive ingredients are stored in airtight packaging under protective, gas. Substantial amounts of stabilizers are added during the formulating process of, such pharmaceutically active ingredients. In order to have a stable composition of compounds of formula (I), which meets the regulatory requirements, therefore, special packaging conditions will be required which is costly, difficult to manage and difficult to use in an industrial scale. Therefore, it is necessary to develop an alternate formulation which can stabilize the compound of formula (I) such that the expensive packaging requirements can be overcome.
WO 2012/104869 provides a therapeutic compound of formula (I) and their pharmaceutically acceptable salts for the prevention and treatment of lipodystrophy caused because of HIV infection or combination therapy of HIV-1 protease inhibitors (Pis) and/or reverse transcriptase inhibitors (nRTIs) by neutralizing lipohypertrophy, lipoatrophy and metabolic abnormalities in HIV patient. However, this document D1 does not disclose an alkalizing agent.
The inventors of the present invention surprisingly found that when suitable alkalinizer(s) are added into the formulation, the formulation remains stable. Further, one of the impurity (sulfoxide) which was being generated in API increases from 0.17% to 0.76% over a period of 6 months. Surprisingly, when suitable alkalinizer(s) are added which maintains the pH of the formulation above 7, the increase in the level of said impurity is restricted (from 0.13% to 0.26% over six months with no further increase with time). Therefore stabilization of compositions containing compounds of formula (I) can be made by maintaining the microenvironmental pH of composition above 7 by using suitable alkalinizers. Use of a suitable antioxidant(s) and chelating agent(s) further stabilizes the formulation.